Abstract
BackgroundDuring pregnancy asthma may remain stable, improve or worsen. The factors underlying the deleterious effect of pregnancy on asthma remain unknown. Oxytocin is a neurohypophyseal protein that regulates a number of central and peripheral responses such as uterine contractions and milk ejection. Additional evidence suggests that oxytocin regulates inflammatory processes in other tissues given the ubiquitous expression of the oxytocin receptor. The purpose of this study was to define the role of oxytocin in modulating human airway smooth muscle (HASMCs) function in the presence and absence of IL-13 and TNFα, cytokines known to be important in asthma.MethodExpression of oxytocin receptor in cultured HASMCs was performed by real time PCR and flow cytomery assays. Responses to oxytocin was assessed by fluorimetry to detect calcium signals while isolated tracheal rings and precision cut lung slices (PCLS) were used to measure contractile responses. Finally, ELISA was used to compare oxytocin levels in the bronchoalveloar lavage (BAL) samples from healthy subjects and those with asthma.ResultsPCR analysis demonstrates that OXTR is expressed in HASMCs under basal conditions and that both interleukin (IL)-13 and tumor necrosis factor (TNFα) stimulate a time-dependent increase in OXTR expression at 6 and 18 hr. Additionally, oxytocin increases cytosolic calcium levels in fura-2-loaded HASMCs that were enhanced in cells treated for 24 hr with IL-13. Interestingly, TNFα had little effect on oxytocin-induced calcium response despite increasing receptor expression. Using isolated murine tracheal rings and PCLS, oxytocin also promoted force generation and airway narrowing. Further, oxytocin levels are detectable in bronchoalveolar lavage (BAL) fluid derived from healthy subjects as well as from those with asthma.ConclusionTaken together, we show that cytokines modulate the expression of functional oxytocin receptors in HASMCs suggesting a potential role for inflammation-induced changes in oxytocin receptor signaling in the regulation of airway hyper-responsiveness in asthma.
Highlights
Oxytocin, a hypothalamic neuropeptide, induces uterine contractions during parturition and milk ejection during lactation via activation of the oxytocin receptor, a G protein-coupled receptor [1]
PCR analysis demonstrates that oxytocin receptors (OXTR) is expressed in HASMCs under basal conditions and that both interleukin (IL)-13 and tumor necrosis factor (TNFa) stimulate a time-dependent increase in OXTR expression at 6 and 18 hr
Oxytocin levels are detectable in bronchoalveolar lavage (BAL) fluid derived from healthy subjects as well as from those with asthma
Summary
A hypothalamic neuropeptide, induces uterine contractions during parturition and milk ejection during lactation via activation of the oxytocin receptor, a G protein-coupled receptor [1]. Whether oxytocin plays a role in lung diseases remains unknown. A direct action of estrogen on airway smooth muscle function has been recently reported as a plausible molecular mechanism linking sex hormone and disease worsening [12]. Other circulating pregnancy-associated factors exert detrimental effects on asthma by modulating airway smooth muscle function. The oxytocin receptor is expressed in the lungs [16], whether oxytocin plays a role in airway diseases remains unknown. Additional evidence suggests that oxytocin regulates inflammatory processes in other tissues given the ubiquitous expression of the oxytocin receptor. The purpose of this study was to define the role of oxytocin in modulating human airway smooth muscle (HASMCs) function in the presence and absence of IL-13 and TNFa, cytokines known to be important in asthma
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